ABSTRACT Development of new therapies, especially in the era of targeted treatments and personalized medicine, is typically driven by understanding the underlying biology, molecular biology and biochemistry of tumor cells and their surrounding microenvironments targeting genetic alterations. This is a common theme in drug discovery and can provide specificity, but cannot generally provide comprehensiveness in targeting. Cancer cells can evolve that lack the targeted genetic alterations or that are resistant, and could cause progressive disease. Therefore, it is essential to expand our armament of therapies, but more importantly to re-evaluate our concept of limiting therapies to targets rarely altered in extremely heterogeneous diseases such as ovarian cancer. The evolutionary nature of cancer implies, contrary to conventional wisdom, that the essential features of any therapy for the consistent cure or control of cancer must be independent of the particular pathways of tumor cell evolution and independent of any particular genetic or epigenetic alterations. Although the genetic and epigenetic complexity of cancer is nearly unlimited, tumor cell evolution is constrained. A malignant cell will result, if and only if, the alterations cause normal cellular machinery to carry out the processes of proliferation and invasiveness. Current drug discovery efforts tend to focus on commonly mutated signal transduction pathways, e.g., a series of growth factor receptors and downstream modulators (phosphatases and kinases) that are working in concert to promote growth but are not the cell's central machinery. To identify the Achilles' heel of ovarian cancers, we designed an RNA-based screen to identify putative points of molecular vulnerability (targets essential for cell survival). These screens identified KIF11 as an essential protein in maintaining tumor cell viability. KIF11 encodes kinesin Eg5 (KIF11), a motor protein required for microtubule antiparallel sliding during mitosis that has been targeted clinically via ispinesib (SB-715992), an allosteric small-molecule inhibitor. Although well tolerated, the clinical response rates were typically less than 10% in heavily treated patients with advanced disease. We hypothesize that one mechanism through which ispinesib efficacy is muted is via a compensatory pathway involving KIF15, a second motor kinesin based on KIF15 cooperation with and functional compensation for KIF11 function during mitotic spindle assembly. Using a synthetic lethal approach, we have shown that silencing of KIF15 or its binding partner, TPX2, dramatically sensitized cells to KIF11 inhibitors. Based on these data, we strongly believe that compounds interfering with KIF15-TPX2 interactions will greatly enhance the clinical efficacy of existing KIF11 inhibitors, thereby creating new treatment options for women with recurrent disease. Proposed are studies that will bridge the gap between identifying a clinically relevant therapeutic target and implementing pharmacologic intervention in ovarian cancer patients.